Transplantation has emerged as the preferred method of treatment for many forms of end-stage organ failure. While short-term results have improved long-term outcomes remain inadequate. To maintain their allogralts, patients must rigidly adhere to life-long treatment regimens using costly immunosuppressive agents that dramatically increase the risks of cardiovascular disease, infections and malignancies. The development of strategies to promote the acceptance of allogeneic tissues without the need for chromic immunosupression could not only reduce the risk of these life-threatening complications, but also greatly expand the application of organ, tissue and cellular transplantation for diseases such as the hemoglobinopathies and genetic irnmunodeficiencies, Type I diabetes, and possibly other autoimmune diseases. We have developed a novel non-myelosuppressive protocol using anti-CD4OL and CTLA4-Ig to permit the induction of titratable levels of. In this proposal we will explore the use of alternative immunomodulatory strategies to facilitate the development of chimerism and tolerance, study the interactions of conventional immunosuppressive agents with the tolerance induction approach, explore the mechanisms involved in tolerance maintenance, define the effects of tolerance induction on immunologic memory and study the use of stem cells as alternatives to primary bone marrow preparation.